EP0880967B1 - Nephroprotective drug - Google Patents

Description

The present invention relates to the use of 4-chloro-5 - [(4,5-dihydro-1H-imidazol-2-yl) amino] -6-methoxy-2-methylpyrimidine (= Moxonidine) and its physiologically tolerable Acid addition salts for treatment and / or prophylaxis renal failure in normotensive patients, and the manufacture of medicinal products suitable for this treatment.

The invention has for its object new pharmaceutical Preparations for the treatment of renal failure to develop in normotensive patients.

und dessen physiologisch verträgliche Säureadditionssalze in subantihypertensiven Mengen verwendet. According to the invention, 4-chloro-5 - [(4,5-dihydro-1H-imidazol-2-yl) -amino] -6-methoxy-2-methylpyrimidine is used in the production of pharmaceutical preparations for the treatment of renal insufficiency independent of hypotension in normotensive patients of formula I.

and its physiologically tolerated acid addition salts used in subantihypertensive amounts.

As physiologically acceptable acid addition salts of Moxonidins are suitable salts with inorganic acids, for example Hydrohalic acids, or with organic Acids, for example lower aliphatic mono- or dicarboxylic acids such as acetic acid, fumaric acid or tartaric acid or aromatic carboxylic acids such as B. salicylic acid.

The compounds used according to the invention for the treatment of renal insufficiency independent of hypotension fall under the scope of the 5 - [(2-imidazolin-2-yl) -amino] -pyrimidine derivatives with hypotensive properties described in German Offenlegungsschrift No. 28 49 537 and are not known this patent application known. Pharmaceutical preparations containing moxonidine are commercially available as antihypertensives under the brand name Physiotens ^R and are used medically as antihypertensives. The compounds can be prepared in a manner known per se by the methods described in the aforementioned DOS or analogously to these methods.

It is known that between high blood pressure and chronic Kidney failure interactions exist by on the one hand high blood pressure heavily burdened the kidneys and damage can result in kidney function and on the other hand chronic decreased kidney function often high blood pressure has the consequence. From a study by Mall et al. (Cardiovascular Risk Factors Vol 5, Suppl 1, 1995, pages 33-39) is also known to lower blood pressure (e.g. by application of anti-hypertensive pharmaceutical ingredients, including moxonidine) has a nephroprotective effect and kidney damage can reduce or prevent.

It has now surprisingly been found that moxonidine and its physiologically acceptable acid addition salts already in subantihypertensive doses a nephroprotective effect possess on humans and larger mammals and for slowing down or inhibiting progression from decreased kidney performance to lead. Moxonidine is therefore also suitable for prophylaxis and treatment independent of hypotension Kidney damage and renal failure, e.g. in normotensive Patients. As subantihypertensive doses are in the frame of the present invention referred to cans which none cause physiologically relevant lowering of blood pressure. As Patients become normotensive in the context of the present invention denotes, which are either spontaneously normotensive or by taking other antihypertensive agents were made normotensive. According to the invention one is essentially Antihypertensive treatment with moxonidine (i.e. treatment with doses that are not physiological or cause pharmacologically significant lowering of blood pressure) used to prevent or relieve kidney disease and can renormalize damaged kidney architecture promote.

For the treatment of renal failure according to the invention can moxonidine and its physiologically acceptable acid addition salts in usual pharmaceutical preparations orally, intravenously or transdermally.

So subantihypertensive nephroprotective can Amounts of the compounds according to the invention together with usual pharmaceutical auxiliaries and / or carriers in solid or liquid pharmaceutical preparations may be included. As Examples of solid preparations are preparations that can be administered orally such as tablets, coated tablets, capsules, powders or granules or suppositories. These solid preparations can pharmaceutically customary inorganic and / or organic carriers such as B. milk sugar, talc or starch in addition customary pharmaceutical auxiliaries, for example lubricants or tablet disintegrants. Liquid preparations such as solutions, suspensions or emulsions of the active ingredients can use the usual diluents such as water, oils and / or suspending agents such as polyethylene glycols and the like contain. Additional auxiliary substances can also be used be added such. B. preservatives, flavor corrections and the same.

The active ingredients can with the pharmaceutical auxiliary and / or Carriers mixed in a conventional manner and be formulated. For the production of solid dosage forms can the active ingredients, for example, with the auxiliary and / or Carriers mixed in the usual way and wet or dry be granulated. The granules or powder can be directly in Capsules filled or in the usual way to tablet cores be pressed. If desired, these can be known To be coated.

The nephroprotective effect of moxonidine in the subantihypertensive Dose range was assessed in standard animal studies Rats detected.

According to the invention, cans are considered subantihypertensive cans used in a dose range in which the treated Species no pharmacologically relevant hypotensive Effects occur. To study the influence of subantihypertensive doses of moxonidine on progression of renal insufficiency this was used as an experimental model animal model of the subtotal nephrectomized known for kidney damage Rat used. This was considered general accepted surrogate marker for the degree the kidney damage that has occurred or a reduction in kidney performance the glomerulosclerosis index is determined.

test description

Male Sprague-Dawley rats were fed a diet which contained 40 g protein and 0.6 g NaCl per 100 g. To After an adaptation period of 7 days, a subtotal nephrectomy was performed performed. This was done in a first operation in short-term anesthesia (ketamine / xylazine i.m.) by clamping and Ligate the renal artery and move the kidney capsule To preserve the adrenal gland, a right nephrectomy was performed. After 5 days, at a time when a compensatory Left kidney hypertrophy has occurred was anesthetized in a second operation (ketamine / xylazine i.m.) resection of the upper and lower poles of the left Kidney performed. From the 3rd day after the second operation was a group of 10 animals over the entire study period of 12 weeks of moxonidine in a daily dose 1.5 mg / kg via the feed pellets p.o. applied. A Control animal group received the same diet without moxonidine, being ensured via a pair feeding protocol was that treated and untreated animals the same amount of feed ingested. In some of the experimental animals (4th Animals per experimental group), a permanent control of the Blood pressure. The acquisition of the blood pressure parameter was done with the help of telemetric data transmission (Data Sciences International, St.Paul, MN, USA). To the rats received a pressure catheter connected to a transmitter implanted in the abdominal aorta.

At the end of the test, the anesthesia (ketamine / xylazine i.m.) Kidneys after perfusion fixation after quantitative stereological Methods worked up. For this purpose, a catheter was placed in the Abdominal aorta introduced. The vascular system was over this Catheter after washing out with a dextran solution (Rheomakrodex; Schiwa Co., Glandorf) for 12 minutes with a 0.2 molar Phosphate buffer containing 3% glutaraldehyde in one Perfusion pressure of 110 mmHg fixed. The kidneys were weighed and cut into 1 mm thick slices. The slices were embedded in paraffin, cuts were 4 µm thick made and stained with hematoxilin / eosin. The Glomerulosclerosis index was light microscopic by the method by Raij et al. (Raij L, Azar S, Keane W. Kidney Int. 1984; 26: 137-143). It was in at least 1000 Glomerular sclerosis corresponding to the affected areas divided into severity levels from 0 to 4 (0 = no damage; 1 = up to 25%; 2 = 25 to 50%; 3 = 50 to 75%; 4 = 75 to 100%).

The test results are shown in the table below. The values for the glomerulosclerosis index given in the table are mean values +/- standard deviation of the measurement in 10 animals each. The blood pressure values are mean values +/- standard deviation of the telemetric blood pressure measurement in 4 animals each. The pressure values are given as mean systolic blood pressure over 24 hours in the 1st and 9th week of treatment.

The above test results show that under Moxonidine treatment with approximately constant blood pressure values the glomerulosclerosis index is reduced by over 40%. This is an indication of the inhibitory effect of moxonidine on progression of decreased kidney performance and kidney damage.

This is why moxonidine and its acid addition salts are used prophylaxis and treatment independent of hypotension Suitable for renal insufficiency. The cans to be used can be individually different and naturally vary depending on Type of condition to be treated and form of application. In general, however, are suitable for oral applications larger mammals, especially humans, with dosage forms an active substance content of 0.05 to 0.2 mg per single dose.

The following example is intended to produce a treatment of moxonidine suitable for renal failure explain pharmaceutical preparation in more detail, but without limit the scope of registration.

Example 1: Moxonidine-containing film-coated tablets

Composition: Tablet cores: moxonidine 0.010 parts lactose 9,590 parts Povidone USP 0.070 parts Crospovidone USP 0.300 parts magnesium stearate 0.030 parts (Water 0.750 pieces) Total solids 10,000 parts Film-coating: hydroxypropyl methylcellulose 0.156 parts 30% aqueous ethyl cellulose dispersion 0.480 parts (Δ solid) (0.144) parts Polyethylene glycol 6000 0.030 parts Titanium dioxide 0.150 parts Talc 0.1197 parts Red iron oxide 0.0003 parts (Water 3,864 pieces) Total solids 0.600 parts Total amount of film coating suspension 4,800 parts

For coating 10,000 tablet cores, each weighing 100 mg 4.8 kg of the above film coating suspension are used.

Tablet core production:

The moxonidine and lactose were mixed. The mixture was made with a solution of the binder Povidone in water moistened, well kneaded and the product obtained was spread out on hordes and at a temperature of approx. 50 ° C up to a moisture content of at most 0.5% dried. The dried product was removed by a 0.75 mm sieve (Frewitt machine) passes. After mixing of the granules obtained with crospovidone and magnesium stearate it became tablet cores with a weight of 100 mg pressed so that each tablet core contained 0.1 mg of active ingredient.

Production of the film coating suspension:

The hydroxypropylmethyl cellulose and the polyethylene glycol 6000 were dissolved in part of the water. About this solution was a suspension of talc, titanium dioxide and iron oxide added to the rest of the water with stirring. The received Suspension was stirred with the 30% diluted aqueous ethyl cellulose dispersion.

Coating the tablet cores:

The film coating suspension was applied to the tablet cores a filming apparatus sprayed while warm air from approx. 70 ° C the tablet cores to a temperature of approx. Heated to 45 ° C. Then the film-coated tablets Dried for 16 hours at a temperature of approx. 45 ° C.

Claims (4)

1. The use of a sub-antihypertensive quantity of the compound 4-chloro-5-[(4,5-dihydro-1H-imidazol-2-yl)-amino]-6-methoxy-2-methylpyrimidine of Formula I

   

   or the physiologically compatible acid addition salts thereof for the preparation of pharmaceutical preparations for the prophylaxis and/or treatment of kidney damage and/or of renal failure in normotensive patients.
2. The use according to Claim 1, characterised in that the normotensive patients are spontaneously normotensive or are rendered normotensive by a hypotensive agent other than the compound of Formula I or its physiologically compatible acidaddition salts.
3. The use according to Claim 1, characterised in that the compound of Formula I or the physiological [sic] acid addition salts thereof [are used] for the preparation of oral pharmaceutical preparations, preferably in a subantihypertensive quantity of 0.05 to 0.2 mg per individual dose.
4. A method for the preparation of pharmaceutical preparations for the prophylaxis and/or treatment of kidney damage and/or renal failure in normotensive patients, characterised in that a sub-antihypertensive nephroprotective quantity of the compound of Formula I according to Claim 1 or the physiologically compatible acid addition salts thereof together with conventional pharmaceutical auxiliaries is converted into a suitable medicament form.